Bottle pressurization delivery system

ABSTRACT

A container assembly for use with a high-pressure liquid chromatography (HPLC) instrument is disclosed, in which the container assembly, when coupled to a source of pressurized gas, provides fluid medium to the HPLC instrument at positive pressure. The container assembly has an external exterior container shell, an internal fluid container for holding fluid medium, an interstitial volume between the external exterior container shell and the internal fluid container, a port for fluidly connecting the volume to a pressurized gas source, and a port for fluidly connecting the internal fluid container to the HPLC instrument. As a pressurized gas in the interstitial volume increases, fluid medium flows out of the port connected to the internal fluid bag and container assembly at a positive pressure. A system incorporating the container assembly, and method of use of the same, are also disclosed.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a divisional of U.S. patent application Ser. No.14/213,001, filed on Mar. 14, 2014, now granted as U.S. Pat. No.9,921,193, which claims the benefit of priority to U.S. ProvisionalPatent Application No. 61/785,000, filed on Mar. 14, 2013, which areherein incorporated by reference in their entirety for all purposes.

BACKGROUND OF THE INVENTION

The present invention resides in the field of high-pressure, orhigh-performance, liquid chromatography (HPLC) assays, particularly forthe delivery of reagents, diluents, solvents, and other fluids an HPLCinstrument and apparatus system. More specifically, the presentinvention is directed to a fluid handling system for the delivery ofsolvent fluids with positive pressure to an HPLC instrument.

HPLC is a chromatographic technique used to separate a mixture ofcompounds in analytical chemistry and biochemistry with the purpose ofidentifying, quantifying or purifying the individual components of themixture. Generally, HPLC relies on pumps to pass a pressurized liquidand a sample mixture through a column filled with a sorbent, leading tothe separation of the sample components. The active component of thecolumn, the sorbent, is typically a granular material made of solidparticles. The components of the sample mixture are separated from eachother due to their different degrees of interaction with the sorbentparticles. The pressurized liquid is typically a mixture of solvents(e.g. water, acetonitrile, methanol) and is referred to as “mobilephase”. In addition to the composition and temperature of the mobilephase, the fluid pressure of the mobile phase plays a major role in theseparation process by influencing the interactions taking place betweensample components and sorbent. These interactions are physical innature, such as hydrophobic (dispersive), dipole-dipole and ionic, mostoften a combination thereof.

HPLC instruments and techniques have become increasingly sophisticatedand complex, allowing for the analysis of multiple portions of a sample,utilizing a variety of different solvent fluids or analyzing a varietyof samples with the same or different solvents. Such systems requirefluid distribution systems capable of allocating precise amounts ofsolvents at specific pressures, for extended durations of time, and theability to switch from one solvent to another.

HPLC systems known in the field often require that the solvent fluids tobe used by the instruments be elevated, so as to take advantage ofgravity, drawing down the solvent fluids into the instrument, and thuspriming the fluid lines of the HPLC instrument.

In view of the above, there remains a need to provide solvents to HPLCinstrumentation without the disadvantages noted above and known in thefield.

BRIEF SUMMARY OF THE INVENTION

Embodiments of the present disclosure are directed to a pressurizedsystem for the delivery of fluid mediums, such as solvent fluids, intoan HPLC instrument, and to modules within an HPLC instrument such as apump set, a separation module, or a dilution module. An array of bottles(also referred to as “reagent boxes” or “container assemblies”) eachcontain an enclosed bag or pouch, within which solutions of solvents,reagents, buffers, diluents, and/or other fluid mediums are contained.The interstitial volume of space between the bag the inside of thebottles is then pressurized with a gas, such as air. The increased gaspressure exerts force on the exterior of the bag, encouraging the egressof fluid medium, such as solvent fluid, from the enclosed bag throughfluid connectors. The fluid connectors lead into the HPLC instrument andthus the present disclosure provides solvent fluids to an HPLCinstrument and system at a positive pressure, relative to ambientconditions.

Some embodiments of the present disclosure include shut-off valves onthe fluid connectors of the bottles prevent fluid egress when the bottleis outside of or not properly coupled to an HPLC instrument. Shut-offconnectors are also used on the HPLC instrument in order to prevent theaspiration of air by pumps if a bottle is not connected. Each bottleposition on the HPLC instrument has an individual valve forpressurization and depressurization, which is fed from a centralizedreservoir and releases to ambient atmosphere. In the case of a bagfailure causing the volume of space in the bottle to fill withpressurized fluid, the valves vent away from the electronics within theHPLC instrument, into drip trays. The bottles may be made of metal,plastic, reinforced materials, or another appropriate rigid orsemi-rigid materials, in order to generally maintain the form of thebottles when under pressure. In aspects, the structural walls of suchbottle can restorably flex, expanding to a degree when under pressureand returning to a base, unexpanded state when not under pressure. Abottle may reside within an additional external housing, to assist inmaintaining the form of and reinforce the bottles when under pressure.

Further embodiments of the present disclosure allow for providing fluidat a positive pressure to an instrument without the need for additionalelevation in order to prime the system. The positive pressure alsofacilitates the use of a forward pressure degassing system, whichrequires no pump. The combination of positive pressure in the reagentconsumable, coupled with the debubblers in the bulk fluids module of thepresent system, enables the consumables to be connected to the systemeasily without injecting bubbles of air into the fluidic system.

Some embodiments of the present disclosure comprise a container assemblyfor holding an fluid medium, the container assembly comprising: anexternal container having a first port and a second port, the externalcontainer defining a volume fluidly connected to the first port; and aninternal container contained within the external container and beingfluidly sealed from the volume, the internal container holding an fluidmedium and being fluidly connected to the second port by way of a valve.

Further embodiments of the present disclosure comprise a method ofhandling fluid medium within an instrument, comprising: holding aninternal container within an external container, the external containerdefining a volume fluidly sealed from the internal container; holding anfluid medium within the internal container; coupling a first port to theexternal container to a pressurization system of the instrumentcompressing the internal container by filling the volume withpressurized gas through the first port; coupling a second port to theinternal container to a system of an instrument; and delivering thefluid medium from within the internal container at a positive pressureto the instrument through the second port.

Some embodiments of the present disclosure comprise a system for thehandling of an fluid medium in an instrument, comprising: a gas intakeand pressurization apparatus; a plurality of container assemblies, witheach container assembly comprising an external container having a firstport and a second port, each external container defining the firstvolume fluidly connected to the first port, and an internal containerdefining the second volume contained within the external container andbeing fluidly sealed from the first volume, with each first volume beingfluidly connected to the gas intake and pressurization apparatus, andwith each second volume holding an fluid medium; and an instrumentfluidly connected to each container assembly second volume, such thatfluid medium from each container assembly can enter the instrument.

It is to be noted that while the present disclosure is generallydirected to HPLC instrumentation and chemistries, the pressurized systemfor the delivery of fluid medium can be used for any appropriatelydesigned chemistry or biochemistry instrument that requires thepressurized delivery of reagents, buffers, diluents, solvents, or otherfluid mediums.

BRIEF DESCRIPTION OF THE DRAWINGS

Illustrative aspects are described in detail below with reference to thefollowing drawing figures.

FIG. 1 is an architectural schematic of the reagent box, according tosome embodiments.

FIG. 2 is an exploded-view illustration of the reagent box and itscomponent parts, according to some embodiments.

FIG. 3 depicts a design flowchart illustrating the interaction andconnections between aspects of the bulk fluidics module, according tosome embodiments.

FIG. 4 is a detail schematic illustration of the consumablepressurization system, according to some embodiments.

FIG. 5A is a cross-sections schematic illustration of a containerassembly, according to some embodiments.

FIG. 5B is a schematic illustration of the reagent consumable region,leak detection region, reagent decompression region, fluid combinerregion, buffer conditioner, and diluent conditioner, and the fluid flowthrough these regions, within the bulk fluidics module, according tosome embodiments.

FIG. 6 is a schematic illustration of the waste handling assembly of thebulk fluidics module, according to some embodiments.

FIG. 7A is an illustration of an HPLC instrument with containerassemblies, according to some embodiments.

FIG. 7B is an illustration of a container assembly, according to someembodiments.

DETAILED DESCRIPTION OF THE INVENTION

The present disclosure is directed to a pressurized system for thedelivery of fluid mediums into an HPLC instrument and system, wherein abottle, or reagent box, is used to store and supply solvents. Thereagent box is designed for simple and efficient loading and lockinginto an HPLC instrument, minimizing the time and work required toreplenish reagents on an HPLC instrument. The reagent box may alsoimprove the shelf life of the solvents stored within the reagent box.

As used herein, the term “fluid medium” can refer to any one of areagent solution, a buffer solution, a solvent, a diluent, a samplefluid (such as blood, urine, or other biological fluids), and/or otherfluids. Such fluid mediums can be those that are used, or known in theart to be used, as part of a mobile phase in HPLC instrumentation. Inalternative embodiments, fluid mediums, and the pressurized delivery offluid mediums, can be applied toward general life science or diagnosticresearch fluidic instrumentation, such as instrumentation for ionexchange chromatography, protein purification, solid phase extraction,liquid-liquid extraction, distillation, fractional distillation, fluidseparation, magnetic separation, stripping, membrane or mesh filtration,flocculation, elutriation, leaching, or other such instrumentation. Insome aspects, the fluid medium can be an HPLC solvent, i.e. a fluidspecific for use with HPLC instrumentation. In further aspects, thefluid medium can be fluids used in separation techniques, filtrationtechniques, extraction techniques, purification techniques, distillationtechniques, flocculation techniques, elution techniques, leachingtechniques, or the like. Exemplary fluid mediums include, but are notlimited to, water, acetic acid, acetone, acetonitrile, carbondisulphide, carbon tetrachloride, chlorobenzene, chloroform,cyclohexane, cyclopentane, dichloromethane, 1,2-dichloroethane, diethylether, dimethylformamide, dimethylsulfoxide, dioxan, ethanol, ethylacetate, fluoroalkanes, heptane, hexane, methanol, methyl ethyl ketone,m-xylene, n-butyl acetate, n-butyl ether, nitromethane, n-methylpyrollidone, pentane, petroleum ether, 1-propanol, 2-propanol, pyridine,tetrahydrofuran, toluene, triethylamine, 2,2,4-trimethylpentane, andcombinations, mixtures, and variations thereof.

The use of the reagent box further allows for easy identification of thereagent fluid contained within the bottle. This can be accomplished bycolor-coding the reagent box itself. In addition or alternatively, thereagent box can be barcoded, QR-coded, or otherwise labeled withidentifying data. Further, the identity of an individual reagent box canbe stored in a computerized database linked to a fluid instrumentsystem, such as a HPLC system, so as to keep track of how much fluidmedium has been dispensed from any given reagent box. Informationregarding the content and/or volume of fluid medium remaining in abottle can be disclosed to a user of an instrument by use of indicatorlights. In aspects, such indicator lights can indicate that the amountof fluid medium remaining in a bottle is sufficient, that the amount offluid medium remaining in a bottle is of concern, and/or that there isno fluid medium remaining in the bottle. Information regarding thecontent and/or volume of fluid medium remaining in a bottle, and alsoinformation regarding the number of tests run on an instrument with thebottles, can be stored, displayed, and/or manipulated on a computersystem coupled with the fluid instrument system. A barcode reader or aQR-code reader may also be connected to a computer system coupled with afluid instrument system and provide for data entry of the informationbarcoded or QR-coded on a reagent box.

In further aspects, a reagent box can include a non-transitorycomputer-readable memory component that can store information regardingthe volume of fluid medium held in the reagent box. The non-transitorycomputer-readable memory can be updatable, such that as fluid mediumdecreases in the reagent box, the amount of remaining fluid medium inthe box is updated to store information regarding the actual amount offluid medium in the reagent box. Accordingly, if the reagent box istransferred from one fluid instrument system to a subsequent fluidinstrument system, the subsequent fluid instrument system can obtaininformation regarding the amount of fluid medium in the reagent box fromthe non-transitory computer-readable memory component. In some aspects,the non-transitory computer-readable memory component can be updatedusing RF transmission from the fluid instrument system, for example,using RFID. In other aspects, the non-transitory computer-readablememory component can be electronically coupled to a fluid instrumentsystem, and thereby updated, when the reagent box is mechanicallycoupled to the fluid instrument system.

The present disclosure also provides for the ability to change thebuffer and reagents as the HPLC instrument is operating, i.e.on-the-fly, simply by swapping out reagent boxes. This can allow for alonger operation time of a fluidic instrument consuming fluid mediums,since reagent, solvent, diluent, and buffer fluids can be replenished asneeded. When a reagent box is swapped out, air may fill the spacebetween the fluid connections on the reagent box and the HPLCinstrument. However, a debubbler, such as a porous membrane allows gasto pass through but not liquid, positioned on the HPLC side of the fluidconnection can be used to prevent air bubbles or pockets from enteringthe fluidic system.

Many embodiments also provide for the advantage that the containerassemblies can be loaded onto an HPLC instrument horizontally, in acantilever orientation. This allows for an HPLC instrument configurationand design which does not require fluid mediums or other fluids to be atan elevated position on an instrument. Such embodiments can provide forthe delivery of fluid mediums at a positive pressure, thus removing theneed to use gravity to drawn down fluid medium fluids into the fluidlines of an instrument, e.g. in order to prime the lines of aninstrument.

While the bottles holding fluids are referred to herein as “reagent”boxes, it is to be understood that the fluid contents of a reagent boxcan include reagents, diluents, buffers, water, solvents, or any otherappropriate fluid medium.

FIG. 1 is an architectural schematic of the reagent box and itscomponent parts 100. The reagent box shell 110 of the reagent box can bemade of metal, plastic, polymer, metal-reinforced polymer, or otherappropriate materials that can both protect the contents in the interiorof the reagent box and withstand stresses related to handling andstorage. Accordingly, in aspects, the reagent box can be rigid orsemi-rigid, particularly when considered relative to a fluid bag 102. Insome aspects, the reagent box can be referred to as an externalcontainer. The fluid bag 102 can be made of a flexible material thatholds a fluid medium, and of a size that fits within the interior of thereagent box shell 110. In aspects, the flexible material can be anelastic, an inelastic, or a semi-elastic polymer material. In furtheraspects, the fluid bag 102 can be referred to as an internal container.The interstitial volume 104 (alternatively referred to as a firstvolume), being the space in between the interior surface of the reagentbox shell 110 and the exterior surface of the fluid bag 102, can befilled with a gas. A gas, such as air, can be pumped into interstitialvolume 104 through a gas interface port 108. As gas fills interstitialvolume 104 of a sealed reagent box, the pressure from the gas enteringthe volume of the reagent box can push fluid medium inside the fluid bag102 out through any egress that exists in the reagent box, primarilythrough the fluid interface port 106. In some aspects, the volume of thefluid bag 102 can be referred to as second volume. A reagent box shell110 can be sealed with a reagent box cap 114 that fits over the open endregion 112 of the reagent box shell 110. The reagent box cap 114 furtherincludes a fluid interface connector 116 which can couple to the fluidinterface port 106, and a gas interface connector 118 which can coupleto the gas interface port 108. The gas interface connector 118 whenconnected to the gas interface port 108 forms a pathway that allows forgas to be pumped into the interstitial volume 104 of the reagent boxshell 110. The fluid interface connector 116 when connected to the fluidinterface port 106 forms a pathway that allows for fluid to exit thefluid bag 102, which in operation is designed to be in response to theincreased gas pressure of the interstitial volume 104 pushing on theexterior surface of the fluid bag 102. An interface plate 120 surroundsand secures a cross-section of the fluid interface connector 116 and gasinterface connector 118 to the fluid bag 102.

FIG. 2 is an exploded-view illustration of the reagent box 200. Thereagent box shell 202, as noted above, can be made of materials that canboth protect the contents in the interior of the reagent box and hold upto external stresses of handling and storage. Further, the reagent boxshell 202 can be molded, contoured, or constructed in order to fit andinterface with an HPLC instrument, or other fluidic instrument, as wellas in order to be easily handled by a user. The fluid bag 204, which canbe made of any appropriate flexible material capable of holding fluid,can be shaped and/or contoured to fit within the reagent box shell 202.The fluid bag 204 can be made of materials that are biologically inertand chemically inert, capable of withstanding the range of solvents,acids, bases, and other liquids that can have corrosive characteristics.Further, the fluid bag 204 can be shaped, tapered, and/or contoured toefficiently allow solvents to egress the fluid bag 204 through the fluidinterface port 208 (alternatively referred to as a nozzle) when theexterior surface of the fluid bag 204 is under pressure. The shaping ortapering of the fluid bag 204 can mitigate against solvents being pushedto the sides, corners, or back of the fluid bag 204 when under pressure,by channeling or directing the held fluid medium toward the exit of thefluid bag 204 at the fluid interface port 208. The fluid mediumaccordingly exits the fluid bag 204 at a positive pressure. This canhelp to maximize the use of any fluid medium, reagent, buffer, diluent,or other solvent in a fluid bag 204 and minimize the waste of any unusedsolvents. As shown, the fluid bag 204 is bordered by flat edging thatcauses the fluid bag 204 to substantively flatten under pressure.

The reagent box cap 206 can be made of the same material or a differentmaterial as the reagent box shell 202. The reagent box cap 206, whenmechanically coupled with the reagent box shell 202, provides for asealed (i.e. airtight) interstitial volume such that the gas in thevolume between the interior surface of the reagent box shell 202 and theexterior surface of the fluid bag 204 will increase in pressure as moregas is pumped into volume. The seal between the coupled reagent boxshell 202 and reagent box cap 206 should not break as gas pressure inthe interstitial volume increases. The reagent box cap 206 furtherincludes a gas interface port 214 for providing gas to the interstitialvolume. A gas interface port O-ring 216 can be used to help secure thegas interface port 214 to a mechanical structure, such as a pipe ortube, used to channel gas into the reagent box. A fluid interface portO-ring 210 can be used to help secure the fluid interface port 208 as itmechanically couples with the reagent box cap 206, the reagent cap fluidport 220, and fluid interface connector 218. An interface connectorlatch 212 can be used to further secure the connection between the fluidinterface connector 218 as it is seated within the reagent cap fluidport 220 and/or the fluid interface port 208. The fluid interface port208 can be threaded or otherwise molded to mechanically couple with thereagent cap fluid port 220, or to guide and control the flow of fluidsthat egress from the fluid bag 204.

In alternative embodiments, the reagent box or container assembly maynot be built from a severable reagent box cap and reagent box shell. Thereagent box can be constructed from parts that are permanently sealedtogether using methods known in the art. Alternatively, ports may beformed in a single body shell using methods known in the art, throughwhich a fluid bag may be inserted and into which interface connectionscan be installed.

The reagent box shell 202 can further include a label region 222 onwhich a barcode, QR-code, or other identifying marking can be printed oraffixed. A label region 222 can be on any part of the external surfaceof the reagent box shell 202, as appropriate for handling andidentifying the reagent box individually or coupled with an HPLCinstrument.

FIG. 3 is a design flowchart illustrating the interaction andconnections between all aspects of the bulk fluidics module 300. Air (orin alternative embodiments, a gas from a controlled gas supply) is drawninto the bulk fluidics module 300 through the consumable pressurizationsystem 301. The consumable pressurization system 301 pressurizes the airand is sent to the reagent consumable region 302 through pressurized gaschannel 315, which can be a hollow piping, tubing, or the like. Airpressure sensors within the consumable pressurization region 301 monitorthe air pressure, sending that information to the control electronics306. Based on that pressure data, the control electronics 306 sendinstructions to controllers within the consumable pressurization region301 to regulate the air pressure therein. Within the reagent consumableregion 302 there are a plurality of reagent boxes, 302 a, 302 b, and 302d, which can contain fluids such as solvents, reagents, buffer, ordiluent. The pressurized air delivered to the reagent consumable region302 through the pressurized gas channel 315 is more specificallydelivered into the gas receiving structure of each reagent box. Aspressurized gas is pumped into the interstitial volume of a reagent box,fluid medium is pushed (at a positive pressure) out of the fluid baginside the reagent box, out through the leak detection region 310 andinto the consumable decompression region 311. The fluid medium from eachreagent box is pushed through a fluid channel dedicated that fluidmedium. For example, as illustrated in FIG. 3 , fluid channel 312 isdedicated to fluid medium from reagent box 302 a, fluid channel 313 isdedicated to fluid medium from reagent box 302 b, and fluid channel 314is dedicated to fluid medium from reagent box 302 d. In embodiments,there may be more than one reagent box connected to a fluid channel,such that multiple reagent boxes with the same fluid, i.e. the samereagent, the same buffer, etc., can be provided to a single fluidchannel system.

The leak detection region 310 is designed to detect leaks from thereagent consumable region 302. Leaks detected from the reagentconsumable region 302 will be sensed by sensors in the leak detectionregion 310, where the sensors can be thermal-based sensors,voltage-based sensors, current-based sensors, or the like. Upondetection of a leak, the control electronics 306 can operate to triggera warning indicator for a user, reduce or shut off pressurization of thereagent boxes, close valves, or execute other actions to minimize and/orstop further leakage.

The consumable decompression region 311 includes valves within a fluiddistribution region 303 that take in the fluid medium expelled from therelated reagent boxes, and regulates the pressure of each fluid mediumbefore further delivering said fluid mediums to the next stages of anHPLC instrument. From the consumable decompression region 311, the fluidmedium from reagent boxes which are reagents and buffers, such as 302 aand 302 b, are further directed through valves within the fluiddistribution region 303 to a buffer conditioner 304, and then furtherdirected out of the bulk fluidics module 300, such as to a separationmodule of the HPLC instrument. Similarly, the fluid medium from reagentboxes which are diluents 302 d are further directed from the consumabledecompression region 311 through valves within the fluid distributionregion 303 to a diluent conditioner 305, and then further directed outof the bulk fluidics module 300, such as to a dilution module of theHPLC instrument.

Following processing in the separation module and dilution module of theHPLC instrument, waste fluids from the HPLC instrument (i.e. solventsrun through a sorbent column) are returned to the bulk fluidics module300, specifically to the waste combiner subassembly 307. The wastefluids, once combined, can be further shunted to a waste container 308as a separate section of the HPLC instrument and/or a waste pipe 309leading out of the HPLC instrument entirely.

FIG. 4 is a detailed schematic illustration of the consumablepressurization system 400. In many embodiments, air from the atmosphereis drawn into the consumable pressurization system 400, and the HPLCinstrument generally, through an air intake 402. In other embodiments,the gas drawn into the consumable pressurization system 400 may be froma controlled source of a specific gas, such as an inert gas. The airdrawn into the consumable pressurization system 400 then passes throughan air filter 404 which filters out particulate matter, preventing suchmatter from entering the consumable pressurization system 400. Thefiltered air then passes through the air pump 406 and through a checkvalve 408 (i.e. a one-way, non-return valve) into an air reservoir 410.A first air pressure sensor 412, which in aspects can be a pressuregauge for 0.0-2.0 bar, and in other aspects may be a pressure gauge for0.0-4.0 bar, measures the air pressure in the air reservoir 410 andcommunicates that information to the control electronics 306, to whichthe air pressure sensor 412 is electrically connected.

From the air reservoir 410, the air drawn into the consumablepressurization system 400 is directed into a pressure regulator 414. Thepressure regulator 414 is controlled by a pressure regulator controller415, which is in turn electrically connected to the control electronics306. The pressure regulator 414 compresses the air to a specifiedpressure and the pressurized air is measured by a second air pressuresensor 416, which in aspects can be a pressure gauge for 0.0-1.0 bar,and which in other aspects can be a pressure gauge for 0.0-4.0 bar,which is also electrically connected to the control electronics 306. Apressure switch 418, which closes an electrical circuit upon reaching acertain pressure, is also in contact with the pressurized. Upon reachinga pressure within a specific range, the pressure switch 418 can operateto, for example, open a pressure release valve, cause an indicator tocommunicate a signal, allow pressurized gas into the pressurized gaschannel 315, and/or trigger other operations in the bulk fluidics module300, or in the HPLC instrument generally. The pressurized air is thendirected from the consumable pressurization system 400 to the attachedreagent boxes.

FIG. 5A is a schematic illustration of a container assembly 500, whichis also referred to as a reagent box. In embodiments, a pair of reagentboxes can be used for each fluid medium to be run through the HPLCinstrument. Accordingly, FIG. 5A identifies constituent parts of theillustrated reagent box with two numbers which relate to a first andsecond reagent box, respectively, of a pair of reagent boxes containingthe same solvent. Similarly, each element can be further defined with asuffix to identify whether a reagent, buffer, diluent, or other solventis present in the reagent box, to allow for more precise tracking offluid and connections in the present application.

In FIG. 5A the reagent box shell 501/502 surrounds and defines aninterstitial volume 503/504 that contains at least a fluid bag 505/506(e.g. a reagent fluid bag 505 a/506 a or a diluent fluid bag 505 d/506d) which can hold a fluid medium, such as an HPLC solvent. Pressurizedgas 550 (such as air) is pumped from the consumable pressurizationsystem 400 through a gas delivery connector or interface on theinstrument (not shown) and enters the interstitial volume 503/504through the gas interface port 513/514 in the reagent box cap 511/512.As noted in embodiments above, the reagent box cap 511/512 operates as alid that seals the reagent box shell 501/502 and only allows for thepassage of gas through the gas interface port 513/514 and the passage offluid through the fluid interface port 515/516. In such embodiments, thelid can be detachable and re-attachable to the reagent box shell501/502. As pressurized gas fills the interstitial volume 503/504, thepressure on the exterior surface of the fluid bag 505/506 increases,reducing the volume of the interior of the fluid bag 505/506. Thecoupled reagent box shell 501/502 sealed with the reagent box cap511/512 must be able to withstand the force exerted by the pressurizedgas, retaining their seal. As the volume of the fluid bag 505/506decreases, any fluid medium inside the fluid bag 505/506 accordinglyexits the fluid bag 505/506 if possible, pushed out through the fluidinterface port 515/516 at a positive pressure, which is also within thereagent box cap 511/512, as fluid stream 552/553 into and through afluid receiving connector (not shown) on the instrument. The fluidinterface port 515/516 may also include a shut-off valve, such that whenthe fluid interface port 515/516 is not coupled to an appropriatereceiving connector, fluid medium inside the fluid bag 505/506 isprevented from egressing out of the fluid bag 505/506. If fluid mediumfrom the fluid bag 505/506 exits into the interstitial volume 503/504,the shut-off valve can also operate to prevent leakage of the fluidmedium out of the container assembly 500.

In aspects, the pressurized gas 550 in the interstitial volume 503/504can be pressurized to a pressure of about 0.5 bar, which can causeegress of fluid medium from the fluid bag 505/506 at a correspondingpositive pressure. In various other aspects, the pressurized gas 550 inthe interstitial volume 503/504 can be pressurized to a pressure ofabout 1.0 bar, about 1.5 bar, about 2.0 bar, about 2.5 bar, about 3.0bar, about 3.5 bar, or less than about 4.0 bar. In other aspects, thepressurized gas 550 in the interstitial volume 503/504 can bepressurized to a pressure in the range of about 0.5 bar to 4.0 bar. Insuch aspects, the coupled reagent box shell 501/502 sealed with thereagent box cap 511/512 must be able to withstand the force exerted bythe pressurized gas 550, retaining their seal. In aspects, the containerassembly 500 can be a semi-rigid container, such that the walls of thecontainer assembly 500 can bend or flex in response to the force exertedby the pressurized gas 550.

The container assembly 500 further contains a consumable tag identifier509/510, which can be a non-transitory computer-readable memory, locatedwithin the reagent box shell 501/502, which is electrically connected tothe control electronics 306 and identifies the contents of theparticular reagent box connected to the HPLC instrument. The consumabletag identifier 509/510 may also include other information about thereagent box and the fluid medium contained within, such as the age ofreagents or production information regarding the reagent box and/or itscontents. In some embodiments, the reagent box can further include aconsumable sensor 507/508, located outside of the reagent shell box501/502, which is electrically connected to the control electronics 306and senses the amount of consumable solvent remaining within the fluidbag 505/506. In other aspects, the consumable tag identifier 509/510 canstore information regarding the amount of fluid medium remaining in thefluid bag 505/506, which can be further updated by the HPLC instrument.In such aspects, the HPLC instrument can calculate the amount of fluidmedium remaining in the fluid bag 505/506 based on the amount of fluidmedium sensed by the HPLC instrument entering the bulk fluidics module300. The HPLC instrument can be informationally coupled to theconsumable tag identifier 509/510, through RFID or other wirelessconnection, or through an electronic coupling, and update theinformation regarding the amount of fluid medium remaining in the fluidbag 505/506 as stored in the consumable tag identifier 509/510.

The information from either or both of the consumable tag identifier509/510 and the consumable sensor 507/508 is relayed to the controlelectronics 306, and is used by the control electronics 306 to regulategas and fluid flow through the bulk fluidics module 300. When theconsumable sensor 507/508 or consumable tag identifier 509/510communicates the amount of consumable fluid medium remaining within thefluid bag 505/506 to the control electronics 306, the controlelectronics 306 can further cause indicator lights (not shown) on theinstrument to signal the status of the volume of fluid medium in thecontainer assembly 500. In some embodiments, the control electronics 306can indicate that the amount of fluid medium remaining is sufficient bytriggering a green indicator light to illuminate, that the amount offluid medium remaining is of concern by triggering a yellow indicatorlight to illuminate, and/or that there is no fluid medium remaining inthe bottle by triggering a red indicator light source to illuminate. Inaspects, any color indicator light can be used to indicate the variousstatuses of fluid medium in a container assembly.

FIG. 5B is a schematic illustration of the reagent consumable region520, leak detection region 522, reagent decompression region 528, fluidcombiner region 538, buffer conditioner 542, and diluent conditioner544, and the fluid flow through these regions, within the bulk fluidicsmodule 300. The reagent consumable region 520 has a plurality ofcontainer assemblies 500, as illustrated in FIG. 5A, which can containliquids such as reagents, buffers, and diluents. As described inrelation to FIG. 5A, when pressurized gas 550 from the consumablepressurization system 400 enters the interstitial volume 503/504 of areagent box, a fluid stream 552/553 egresses from the reagent box. Inthe illustration of FIG. 5B, fluid stream 552 a represents a flow ofreagent fluid that egresses from a first reagent box containing thatreagent. Fluid stream 553 a represents a flow of reagent fluid thategresses from a second reagent box containing the same or a differentreagent as the first reagent box containing reagent. It is appreciatedthat in alternative embodiments, a single reagent box containing aparticular reagent, or a plurality of more than two reagent boxes can beused to deliver a particular reagent or reagents into an HPLC system.Fluid stream 552 b represents a flow of buffer fluid that egresses froma first reagent box containing that buffer. Fluid stream 553 brepresents a flow of reagent fluid that egresses from a second reagentbox containing the same or a different buffer as the first reagent boxcontaining buffer. It is appreciated that in alternative embodiments, asingle reagent box containing a particular buffer, or a plurality ofmore than two reagent boxes can be used to deliver a particular bufferor buffers into an HPLC system. Fluid stream 552 d represents a flow ofdiluent fluid that egresses from a first reagent box containing thatdiluent. Fluid stream 553 d represents a flow of diluent fluid thategresses from a second reagent box containing the same or a differentdiluent as the first reagent box containing diluent. It is appreciatedthat in alternative embodiments, a single reagent box containing aparticular diluent, or a plurality of more than two reagent boxes can beused to deliver a particular diluent or diluents into an HPLC system.

The fluid streams from the reagent boxes each flow into and through theleak detection region 522, wherein each type of fluid, reagent, buffer,and diluent, pass into and through a respective leak detection tray andleak detector. Specifically, reagent fluid streams 552 a and 553 a eachpass through a region containing leak detection tray 524 a, wherein anyleakage of reagent fluid will be detected by leak detector 526 a.Similarly, buffer fluid streams 552 b and 553 b each pass through aregion containing leak detection tray 524 b, wherein any leakage ofbuffer fluid will be detected by leak detector 526 b. In the samemanner, diluent fluid streams 552 d and 553 d each pass through a regioncontaining leak detection tray 524 d, wherein any leakage of diluentfluid will be detected by leak detector 526 d. Each of leak detectors526 a, 526 b, and 526 d are electrically connected to the controlelectronics 306 and/or a control system external to the bulk fluidicsmodule. When a leak is detected, an error message can be sent to thecontrol electronics, notifying the user of the HPLC instrument of theleak, continuing operation of the HPLC instrument under sub-optimalconditions, and/or ceasing operation of the HPLC instrument. Inembodiments, the leak detection region includes shut-off valves (notshown) for each connection to a bottle such that if a leak is detected,the valves prevent further fluid from the bottle identified as leakingfrom entering the HPLC instrument. In other embodiments, there may bemore than one leak detection tray and leak detector for each type offluid run through the bulk fluidics module.

The fluid streams continue through the leak detection region 522 and canpass through the consumable decompression region 528. The valves in theconsumable decompression region 528 serve to decompress the pressure ofthe reagent boxes once fluids have been expelled from the reagent boxeswhich, due to being forced out of a fluid bag 505/506 by pressurized gas550, may be deformed such that the walls of the external container arepressed and stuck in the region of the fluid interface due to theremaining high pressure gas in the interstitial volume of the reagentboxes. A plurality of decompression valves in the consumabledecompression region 528 can be in fluid communication with theinterstitial volumes 503/504 of the reagent boxes and operate to releasepressurized gas from those container assemblies 500. In particular, inthe embodiment illustrated by FIG. 5B, consumable decompression valve530 a, which is controlled by consumable decompression controller 534 a,and is electrically connected to the control electronics 306, connectsto a corresponding gas interface port of a container assembly 500 fromwhich reagent fluid stream 552 a flows. Similarly, consumabledecompression valve 532 a, which is controlled by reagent decompressioncontroller 536 a, and is electrically connected to the controlelectronics 306, connects to a corresponding gas interface port of acontainer assembly 500 from which reagent fluid stream 553 a flows.Next, consumable decompression valve 530 b, which is controlled byconsumable decompression controller 534 b, and is electrically connectedto the control electronics 306, connects to a corresponding gasinterface port of a container assembly 500 from which buffer fluidstream 552 b flows. Similarly, consumable decompression valve 532 a,which is controlled by consumable decompression controller 536 a, and iselectrically connected to the control electronics 306, connects to acorresponding gas interface port of a container assembly 500 from whichbuffer stream 553 b flows. Finally, consumable decompression valve 530d, which is controlled by consumable decompression controller 534 d, iselectrically connected to the control electronics 306, connects to acorresponding gas interface port of a container assembly 500 from whichdiluent stream 552 d flows. Similarly, consumable decompression valve532 d, which is controlled by consumable decompression controller 536 d,and is electrically connected to the control electronics 306, connectsto a corresponding gas interface port of a container assembly 500 fromwhich diluent stream 553 d flows. Each of the consumable decompressioncontrollers related to the various reagent, fluid, and diluent fluidsources are specifically connected to valve control circuitry within thecontrol electronics 306.

The fluid streams subsequently enter the fluid combiner region 538wherein each of the reagent, buffer, and/or diluent fluid streams arecombined with like fluids. Specifically, reagent fluid streams 552 a and553 a both enter reagent combiner valve 540 a, which mixes and combinesthe reagents from each fluid stream into a uniform fluid, and outputsthe combined fluid as a single combined reagent stream 554. Similarly,buffer fluid streams 552 b and 553 b both enter fluid combiner valve 540b, which mixes and combines the buffers from each fluid stream into auniform fluid, and outputs the combined fluid as a single combinedbuffer stream 556. In the same manner, diluent fluid streams 552 d and553 d both enter diluent combiner valve 540 a, which mixes and combinesthe diluent from each fluid stream into a uniform fluid, and outputs thecombined fluid as a single combined diluent stream 554. Each of thereagent, fluid, and diluent combiner valves 540 a, 540 b, and 540 d, arespecifically connected to valve control circuitry within the controlelectronics 306.

Combined reagent stream 554 and combined buffer stream 556 are bothdirected from the fluid combiner region 538 into buffer conditioner 542.Both the combined reagent stream 554 and the combined buffer stream 556are then directed from the buffer conditioner 542 to the separationmodule of the HPLC instrument, wherein the streams may be divided and/orrecombined during the HPLC process.

Combined diluent stream 558 is directed from the fluid combiner region538 into diluent conditioner 544. The combined diluent stream 558 isthen directed from the diluent conditioner 544 to the diluent module ofthe HPLC instrument, wherein the stream may be divided and/or recombinedduring the HPLC process.

In an alternative embodiment, the roles of an interstitial volume andfluid bag in a reagent box can effectively be swapped. In suchembodiments, an interstitial volume can be filled with the fluid mediumto provide to an instrument, and an internal container, such as gas bag,can be collapsed and empty when the interstitial volume is filled with afluid medium. The gas bag can be connected to a consumablepressurization system outside of the reagent box through a gas interfaceport and filled with a gas, such as pressurized air. The interstitialvolume can be fluidity connected to a fluid interface port, which canprovide a flow path for the fluid medium in the interstitial volume toenter into an instrument. As pressurized gas fills the gas bag, thevolume of the interstitial volume is reduced, thereby pushing fluidmedium in the interstitial volume out through the egress of the fluidinterface port. In aspects of such embodiments, the gas interface portwith the gas bag can be arranged on a side of the reagent box distalfrom the fluid interface port. In some aspects, filling the gas bag fromthe back of the reagent box forward can cause the fluid medium toadvance toward the fluid interface port. In further aspects, theinterior structure of the reagent box shell can be shaped to channel ordirect fluid medium toward a fluid interface port.

FIG. 6 is a schematic illustration of the waste handling assembly 600 ofthe bulk fluidics module 300. Following operational use in the HPLCinstrument, waste fluids are returned to the bulk fluidics module, andspecifically to the waste combiner, valve, and port subassembly 602. Thewaste combiner, valve, and port subassembly 602 is centered around awaste combiner and valve region 614, which is composed of a waste fluidreservoir 615 and a waste combiner valve 616. Waste diluent fluid 610 issent to the waste fluid reservoir 615 from the HPLC dilution module.Similarly, waste reagent and buffer fluids 612 are sent to the wastefluid reservoir 615 from the HPLC separation module. The waste fluidcontainer 615 has an air intake 608 to provide atmospheric air pressureso that the combined waste fluid 613 smoothly will move through thewaste combiner, valve, and port subassembly 602. The waste combiner,valve, and port subassembly 602 further includes a waste backup sensor618 and a back pressure regulator 620. The waste backup sensor 618,which is connected to the waste data handling circuitry of controlelectronics 306, detects when the combined waste fluid 613 has filledthe waste fluid reservoir 615 to a maximum tolerated volume. The backpressure regulator 620 which is connected to a detection module of theHPLC instrument external to the bulk fluidics module 300, controls theamount of waste fluids 610 and 612 being provided to the waste combiner,valve, and port subassembly 602. The combined waste fluid 613 isdirected from the waste fluid reservoir 615 into the waste combinervalve 616 and is further directed to either the waste container region604 and/or the waste pipe region 606.

Combined waste fluid 613 is directed from the waste combiner valve 616to either a waste container port 624 a or a waste pipe port 628 a.Combined waste fluid that is directed to waste container port 624 apasses through said port, and through the waste container receiver 624b, into waste container 630. A waste container sensor is made up from afirst waste container sensor component 622 a within the waste combiner,valve, and port subassembly 602, a second waste container sensorcomponent 622 b external to but in contact with the waste container, anda third waste container sensor component 622 c inside the wastecontainer. The first waste container sensor component 622 a iselectrically connected to the waste data handling circuitry of controlelectronics 306, and detects when the amount fluid in the wastecontainer 630 reaches a maximum tolerated volume. Combined waste fluidthat is directed to waste pipe port 628 a passes through said port, andthrough the waste pipe receiver 628 b, into waste pipe 632 which leadsoutside the HPLC instrument, ideally to a proper waste disposal system.A waste pipe sensor is made up from a first waste pipe sensor component626 a within the waste combiner, valve, and port subassembly 602 and asecond waste pipe sensor component 626 b which is in contact with thewaste pipe. The first waste pipe sensor component 626 a is electricallyconnected to the waste data handling circuitry of control electronics306, and monitors the flow of waste exiting the bulk fluidics module300.

FIGS. 7A and 7B are illustrations of embodiments of the presentdisclosure. FIG. 7A illustrates an HPLC instrument 700 with dockingstations 702 for container assemblies 704 containing fluid mediums. TheHPLC instrument 700 has indicator lights 706 which can signal to a userthe status of the fluid medium held within the related containerassembly 704 secured within the adjacent docking station 702. Forexample, an indicator light 706 can provide an estimate of how muchfluid medium volume is remaining in the related container assembly 704based on the color of the indicator light. The HPLC instrument 700 canalso have a user interface 708 for monitoring and interacting with theinstrument. FIG. 7A further illustrates how a container assembly 704 maybe horizontally mounted onto and coupled with an HPLC instrument 700. Itis appreciated that in embodiments, solvents can be delivered accordingto operational pressures and requirements to the HPLC instrument 700from a container assembly 704 in the illustrated horizontal orcantilevered orientation. In a horizontal or cantilever orientation,delivery of fluid medium to an instrument does not rely on gravity, thusallowing for the construction of fluidic instruments that do not requiremounting fluid containers proximate to the top of the instrument. Abarcode reader or QR-code reader (not shown) may be connected to theHPLC instrument 700 and be coupled with a computer system incommunication with the HPLC instrument 700 for data input.

FIG. 7B is a cross-sectional illustration of a container assembly 704that may couple with the HPLC instrument 700. The container assembly ismade from an external container 710 which defines a first volume 712 andfurther holds an internal container 714. The internal container 714defines a second volume 716, a volume that can hold solvent, and isfluidly sealed from the external container 710 and the first volume 712.An interface region 718 includes ports that fluidly connect the firstvolume 712 and the second volume 716 of the container assembly 704 tothe appropriate systems of the HPLC instrument 700. The user handlingregion 720 is configured for a user to efficiently handle the containerassembly 704. In aspects, the external container 710 can have agenerally rectangular profile.

In some aspects, computerized components that can operate to control theHPLC instrument can include a processing device which can becommunicatively coupled to the memory device via a bus. The non-volatilememory device may include any type of memory device that retains storedinformation when powered off. Non-limiting examples of the memory deviceinclude electrically erasable programmable read-only memory (“ROM”),flash memory, or any other type of non-volatile memory. In some aspects,at least some of the memory device can include a non-transitorymedium/memory device from which the processing device can readinstructions. A non-transitory computer-readable medium can includeelectronic, optical, magnetic, or other storage devices capable ofproviding the processing device with computer-readable instructions orother program code. Non-limiting examples of a non-transitorycomputer-readable medium include (but are not limited to) magneticdisk(s), memory chip(s), ROM, random-access memory (“RAM”), an ASIC, aconfigured processor, optical storage, and/or any other medium fromwhich a computer processor can read instructions. The instructions mayinclude processor-specific instructions generated by a compiler and/oran interpreter from code written in any suitable computer-programminglanguage, including, for example, C, C++, C#, Java, Python, Perl,JavaScript, etc.

The above description is illustrative and is not restrictive, and as itwill become apparent to those skilled in the art upon review of thedisclosure, that the present invention may be embodied in other specificforms without departing from the essential characteristics thereof. Forexample, any of the aspects described above may be combined into one orseveral different configurations, each having a subset of aspects. Theseother embodiments are intended to be included within the spirit andscope of the present invention. The scope of the invention should,therefore, be determined not with reference to the above description,but instead should be determined with reference to the following andpending claims along with their full scope of equivalents.

What is claimed is:
 1. A bulk fluidics module for a high performanceliquid chromatography (HPLC) instrument, comprising: a gaspressurization system; a reagent consumable region, having a pluralityof gas interface ports and a plurality of fluid interface ports; apressurized gas channel, configured to connect and allow for passage ofgas from the gas pressurization system to the plurality of gas interfaceports; a consumable decompression region, configured to receivepressurized liquids through the plurality of fluid interface ports andto regulate pressure of received pressurized liquids; and a fluiddistribution region, configured to receive liquids from the consumabledecompression region and to direct received liquids out of the bulkfluidics module.
 2. The module according to claim 1, further comprisingcontrol electronics operatively connected with the gas pressurizationsystem, the consumable decompression region, and the fluid distributionregion, and is configured to receive fluid volume information from oneor more container assemblies coupled to the reagent consumable region.3. The module according to claim 2, further comprising a leak detectionregion, operatively coupled to the control electronics, arranged betweenthe plurality of fluid interface ports and the consumable decompressionregion, the leak detection region comprising one or more sensors andconfigured to trigger a warning indicator, a reduction in gas flow tothe plurality of gas interface ports, closing of valves in fluidcommunication with the plurality of fluid interface ports, or acombination thereof.
 4. The module according to claim 3, wherein the oneor more sensors comprise thermal sensors, voltage sensors, electricalcurrent sensors, or a combination thereof.
 5. The module according toclaim 1, further comprising a buffer conditioner configured to receive abuffer fluid from the fluid distribution region and to further directthe buffer fluid to a separation module of the HPLC instrument.
 6. Themodule according to claim 1, further comprising a buffer conditionerconfigured to receive a reagent fluid from the fluid distribution regionand to further direct the reagent fluid to a separation module of theHPLC instrument.
 7. The module according to claim 1, further comprisinga diluent conditioner configured to receive a dilution fluid from thefluid distribution region and to further direct the dilution fluid to adilution module of the HPLC instrument.
 8. The module according to claim1, further comprising a waste container subassembly configured toreceive fluids from a dilution module, a separation module, a detectionmodule, or a combination thereof.
 9. The module according to claim 1,wherein the reagent consumable region configured to mount a plurality ofcontainer assemblies in cantilever.
 10. The module according to claim 1,wherein the reagent consumable region is configured to mount a pluralityof container assemblies, wherein each container assembly has a firstopening configured to couple with one of the plurality of gas interfaceports and a second opening configured to couple with one of theplurality of fluid interface ports.
 11. The module according to claim 1,wherein within the consumable decompression region, pressurized fluidfrom two of the plurality of gas interface ports are combined into asingle fluid stream, wherein the pressurized fluid from the two of theplurality of gas interface ports are the same type of fluid.
 12. Themodule according to claim 1, wherein within the fluid distributionregion, two liquids from the consumable decompression region arecombined into a single fluid stream, wherein two liquids are differenttypes of liquids.